Pathways controlling metabolic and hypertrophic responses in skeletal muscle

Skeletal muscle displays an extensive capacity to adapt to a wide range of metabolic and mechanical stressors. As an insulin-sensitive and exercise-responding tissue, it plays a key role in the context of therapeutic interventions targeting metabolic diseases including type 2 diabetes (T2D) and obesity. The aim of this thesis was to gain mechanistic insight into the adaptive response of skeletal muscle to different genetic and environmental stressors by using in vitro and in vivo models. This work, with a unique in vitro longitudinal model, has allowed the broadening of knowledge about how skeletal muscle adapts to weight-loss surgery. Notably, glucose storage as glycogen, but not fatty acid oxidation was improved in myotubes derived from skeletal muscle biopsies from patients who underwent gastric bypass surgery. Potential new targets mediating the metabolic effects of surgery in skeletal muscle include proline-rich Akt substrate of 40kDa (PRAS40). By genotyping a cohort of individuals with either normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or T2D, the impact of the ACTN3 R577X polymorphism on metabolic disease was evaluated. A higher proportion of T2D patients with the homozygous null allele (577XX) was detected, but no further association with clinical parameters could be established. Rather, the presence of the 577XX genotype is associated with increased mRNA levels of genes involved in structural integrity of skeletal muscle. Surgical removal of synergistic skeletal muscle to induce functional overload and hypertrophy in the plantaris muscle of genetically modified mice addressed whether the γ3 subunit of the energy cell sensor AMPK plays a role in skeletal muscle remodeling in the context of hypertrophy. Following a 14-day functional overload, skeletal muscle of transgenic (R225Q), knockout and wild-type mouse models underwent a similar hypertrophic response, as demonstrated by functional, transcriptional and signaling data. Due to increased mass at baseline, the plantaris muscle of R225Q mice underwent a smaller change in weight gain. Overall, this work demonstrates that the AMPK γ3 isoform is dispensable for skeletal muscle hypertrophy. Collectively, the results presented in this thesis provide new information about the remodeling capacity of skeletal muscle in response to the above-mentioned stressors. Environmental and genetic factors affect skeletal muscle by modifying local signaling pathways and inducing changes in energy metabolism, subsequently impacting whole-body energy homeostasis

Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle

Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. Because skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. Although Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases. We investigated the impact of PKN2 on insulin signaling and glucose metabolism in primary human skeletal muscle cells in vitro and mouse tibialis anterior muscle in vivo. PKN2 knockdown in vitro decreased insulin-stimulated glucose uptake, incorporation into glycogen, and oxidation. PKN2 siRNA increased 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling while stimulating fatty acid oxidation and incorporation into triglycerides and decreasing protein synthesis. At the transcriptional level, PKN2 knockdown increased expression of PGC-1α and SREBP-1c and their target genes. In mature skeletal muscle, in vivo PKN2 knockdown decreased glucose uptake and increased AMPK phosphorylation. Thus, PKN2 alters key signaling pathways and transcriptional networks to regulate glucose and lipid metabolism. Identification of PKN2 as a novel regulator of insulin and AMPK signaling may provide an avenue for manipulation of skeletal muscle metabolism

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema

BACKGROUND: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internetbased survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9 -point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS: A total of 58 worldwide panelists completed both rounds. The fi rst round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of fi ve key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of fi ve key outcomes. Crown Copyright (c) 2024 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol Pract 2024;12:1614-21

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2021 revision and update

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients

The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients

Étude de la régulation du transcriptome du muscle squelettique par l'estradiol et par l'entraînement physique à l'intensité modérée

Le vieillissement et la sédentarité peuvent contribuer à aggraver les facteurs de risque des maladies cardiovasculaires (MCV) et métaboliques. En raison de l'importante influence du muscle squelettique sur le métabolisme énergétique, de la détérioration du profil métabolique et de l'administration de la thérapie hormonale (TH) chez la femme postménopausée, il s'avère impératif de comprendre comment la prise de TH peut modifier le métabolisme énergétique du tissu musculaire à l'intérieur de cette population. Aussi, l'entraînement en endurance permet l'amélioration de plusieurs facteurs de risque modifiables rattachés aux MCV, à l'obésité et au syndrome métabolique. La compréhension des mécanismes moléculaires responsables de ces adaptations bénéfiques, particulièrement chez la personne âgée, demeure toutefois incomplète. Le premier objectif de cette maîtrise était de caractériser les effets aigus d'une injection d'estradiol sur le transcriptome du muscle squelettique de souris femelles ovariectomisées. L'analyse de l'expression génique a montré une modulation distincte à 3 h et 18 h vs. 6 h et 24 h suivant l'injection. Principalement, cette étude suggère la modulation concomitante de transcrits fonctionnellement rattachés à la détermination de la typologie musculaire, à la structure et à la croissance de la fibre musculaire, ainsi qu'au métabolisme énergétique. Le second objectif de cette maîtrise était de caractériser les effets de six semaines d'entraînement à intensité modérée, fixée au seuil lactique (SL), sur le transcriptome du muscle squelettique d'hommes âgés. Cet entraînement a eu pour effet d'améliorer plusieurs paramètres métaboliques tels la capacité aérobie et le taux de lipoprotéines de haute densité (HDL-cholestérol). L'analyse transcriptomique a aussi révélé une transition de la typologie musculaire allant du type rapide vers le type lent, une augmentation du nombre de transcrits codés par l'ADN mitochondrial, ainsi que l'induction de transcrits associés à la matrice extracellulaire et à la phosphorylation oxydative. Ces résultats suggèrent une amélioration du métabolisme des glucides et des lipides chez les hommes âgés suite à l'entraînement en endurance à intensité SL. Finalement, ces deux études ont montré la modulation de transcrits partiellement caractérisés ou non caractérisés à ce jour. Elles contribuent également à l'amélioration de la connaissance des mécanismes d'adaptations du Ill transcriptome du muscle squelettique face à la TH et à l'entraînement en endurance chez l'individu âgé

Synchronization in collectively moving inanimate and living active matter

Abstract Whether one considers swarming insects, flocking birds, or bacterial colonies, collective motion arises from the coordination of individuals and entails the adjustment of their respective velocities. In particular, in close confinements, such as those encountered by dense cell populations during development or regeneration, collective migration can only arise coordinately. Yet, how individuals unify their velocities is often not understood. Focusing on a finite number of cells in circular confinements, we identify waves of polymerizing actin that function as a pacemaker governing the speed of individual cells. We show that the onset of collective motion coincides with the synchronization of the wave nucleation frequencies across the population. Employing a simpler and more readily accessible mechanical model system of active spheres, we identify the synchronization of the individuals’ internal oscillators as one of the essential requirements to reach the corresponding collective state. The mechanical ‘toy’ experiment illustrates that the global synchronous state is achieved by nearest neighbor coupling. We suggest by analogy that local coupling and the synchronization of actin waves are essential for the emergent, self-organized motion of cell collectives